Racemization and enantiomer separation of clopidogrel

ABSTRACT

Processes for separation of enantiomers of clopidogrel, and converting one enantiomer of clopidogrel to another enantiomer of clopidogrel are provided. The enantiomers are separated by crystallizing the (S) enantiomer as camphor sulfonate salt from a hydrocarbon, or a mixture of a hydrocarbon and a co-solvent, preferably DMF:toluene. The (R) enantiomer is then racemized and recycled by reaction with a catalytic amount of a base, preferably with t-butoxide.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.10/302,357, filed Nov. 22, 2002, and claims the priority of U.S.provisional application Ser. No. 60/400,738, filed Aug. 2,2002. Bothapplications are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to the stereochemistry of clopidogrel.

BACKGROUND OF THE INVENTION

Atherosclerosis is the buildup of plaque in the wall of the arteriesleading to a thickening and a reduction in elasticity of the arteries.Atherosclerosis results from injury to the inside layer of the artery.The injury is caused by common activities and diseases such as highcholesterol, high blood pressure, smoking and infection.

Plaques form on the inner walls of the artery at these sites of injury.The plaques are mainly composed of fatty tissue and smooth muscle cells.The formation of plaque often leads to blood clotting due to plateletaggregation at the site of the injury. This clotting may result in areduction or elimination of blood flow to vital organs, causing heartattacks or other serious conditions. The plaque may also rupture andsend a blood clot through the artery, referred to as an embolus, whichif deposited in a smaller blood vessel may completely block blood flow.

Antiplatelet activity is desirable in fighting the often fatal resultsof atherosclerosis. Clopidogrel is an inhibitor of induced plateletaggregation which acts by inhibiting the binding of adenosinediphosphate to its receptor. Clopidogrel is metabolized by the liverinto active form. Its antiplatelet activity is extended in that it stopsany platelet activity even up to ten days after administration.

The chemical name of clopidogrel is methyl(+)-(S)-∝-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate.It has the following structure:

Clopidogrel is disclosed in U.S. Pat. Nos. 4,529,596 (EP 99802, JP59027895), 6,258,961, 5,036,156 (EP 420706, JP 3120286), 6,080,875 (EP971915, JP 2001513806), 6,180,793 (EP 981529, JP 2001525829), FR2769313, all of which are incorporated herein by reference for theirdisclosure and preparation of clopidogrel. U.S. Pat. No. 4,529,596discloses a racemic mixture of clopidogrel and processes for preparingsuch mixture. U.S. Pat. No. 5,036,156 discloses a method for preparingan intermediate in the synthesis of clopidogrel,2-chloro-α-bromophenylacetic acid, and a process for condensing itsmethyl ester with tetrahydrothienopyridine. FR 2769313 discloses anintermediate in the synthesis of clopidogrel,(R)-2-benzenesulfonyloxy-2-(2-chlorophenyl)acetic acid methyl ester, andprocesses for its preparation. FR 2769313 further discloses convertingthe ester to clopidogrel by nucleophilic substitution withtetrahydrothienopyridine. U.S. Pat. No. 5,036,156 discloses preparationof pyridine drivatives by reacting a benzaldehyde with tribromomethaneand potassium hydroxide in water and in the presence of an inertsolvent.

Clopidogrel's platelet inhibiting activity makes it an effective drugfor reducing the incidence of ischemic strokes, heart attacks orclaudication due to vascular diseases such as atherosclerosis. Byinhibiting platelet aggregation, clopidogrel reduces the chance ofarterial blockage, thus preventing strokes and heart attacks. U.S. Pat.No. 5,576,328 describes a method of preventing the occurrence of asecondary ischemic event by administration of clopidogrel, and isincorporated herein by reference.

Recent studies have shown that clopidogrel is more effective in blockingplatelet aggregation than aspirin and is much gentler on thegastrointestinal tract. Clopidogrel is more effective than aspirin evenat much lower dosage. A dosage of 75 mg of base equivalent has beenshown to be more effective than a dosage of 325 mg of aspirin. Inaddition to being more effective, clopidogrel produces much lessgastrointestinal bleeding than aspirin.

Clopidogrel is administered as its bisulfate (syn. hydrogensulfate)salt. Clopidogrel bisulfate has an empirical formula of C₁₆H₁₆ClNO₂S•H₂SO₄. It is currently being marketed as PLAVIX® tablets, whichcontain about 98 mg clopidogrel bisulfate, which is the equivalent of 75mg clopidogrel base. PLAVIX® is a white to off-white powder that ispractically insoluble in water at neutral pH but highly soluble atacidic pH. It dissolves freely in methanol, somewhat in methylenechloride, and poorly in ethyl ether.

The enantiomer (S) clopidogrel is particularly preferred since it is thepharmaceutically active compound.

U.S. Pat. No. 6,080,875 (EP 971915, JP 2001513806), incorporated hereinby reference, prepares (S) clopidogrel by reaction of sodium2-thienylglycidate with (S) 2-chloro phenyl glycine in the presence ofcyanoborohydride.

U.S. Pat. No. 6,180,793 (EP 981,529, JP 2001525819) and relatedpublications WO 98/51681, WO 98/51682 and WO/51689, incorporated hereinby reference, prepare the (S) enantiomer by methods that control thechirality of the intermediates used in the synthesis of clopiodogrel toreduce formation of the (R) enantiomer. U.S. Pat. No. 6,180,793 and therelated art disclose processes for synthesizing (S) clopidogrel byreaction of an activated form of 2-thiophene ethanol with(S)-2-chlorophenyl glycineamide, (S)-2-chlorophenyl-α-amino acetonitrileor (S)2-chlorophenyl glycine methyl ester. After condensation, theresulting compound is cyclicized, hydrolyzed and esterified.

WO 98/39286, incorporated herein by reference, discloses a racemizationprocess for phenyl glycine esters. A mixture of enantiomers of phenylglycine ester is treated with a carbonyl compound in the presence of acarboxylic acid and a single enantiomer of an N-protected a-amino acidas resolving agent. The formation of an imino intermediate causes theracemization of the starting product and the precipitation of a singlediastereomeric salt. After hydrolysis of the salt, an enantiomer ofphenyl glycine ester is obtained.

U.S. Pat. No. 4,847,265 (EP 291459, JP 63203684) discloses methods forseparating one enantiomer of clopidogrel from another by selectivecrystallization of the camphor sulfonate of the (S) enantiomer. The '265patent discloses crystallizing the (S) enantiomer from dimethylformamide(“DMF”), ketones, and alcohols, though crystallization with acetone isprimarily disclosed. U.S. Pat. Nos. 5,132,435 (EP 465358, JP 3055819),6,215,005 and 6,258,961, incorporated herein by reference, also discloseseparating the (S) enantiomer of clopidogrel by crystallization of thecamphor sulfonate from acetone.

U.S. Pat. No. 5,204,469 (EP 466569, JP 4230387) discloses anenantioselective process for synthesis of clopidogrel through reactionof (+)-2-chloro phenylglycine and an activated form of 2-thiopheneethanol followed by cyclization with formaldehyde.

WO 00/27840 (EP 1129087) discloses using a base to racemize an amideintermediate used in the synthesis of clopidogrel. The process of WO00/27840 requires going through an amide intermediate, which is notalways used in preparing clopidogrel, as illustrated by Examples 1 and 2of the present invention. It is advantageous to prepare clopidogrel, andthen racemize clopidogrel rather than the intermediate, and to skip thenecessary conversion of the amide intermediate to an ester as requiredin WO 00/27840. WO 02/059128 also generally discloses racemization of anintermediate of clopidogrel and clopidogrel with an equimolar amount ofa base, though an actual example is not provided regarding racemizationof clopidogrel.

A problem with the preparation of clopidogrel is the presence of atherapeutically inactive enantiomer, the (R) enantiomer. The presence ofthe (R) enantiomer results in contamination of the main product, andreduces the yield by being a waste product. There is a need in the artto prepare the (S) enantiomer of clopidogrel substantially free of the(R) enantiomer in a facile manner suitable on an industrial scale.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a process for preparing(S) clopidogrel free base or a pharmaceutically acceptable salt thereofcomprising the steps of reacting a mixture of (R) and (S) clopidogrelfree base with levorotatory camphor sulfonic acid in a mixture of a C₅to a C₁₂ hydrocarbon and a suitable co-solvent to precipitate (S)clopidogrel camphor sulfonate and converting (S) clopidogrel camphorsulfonate to clopidogrel free base or a pharmaceutically acceptable saltthereof. A preferred salt is the bisulfate salt. Preferably, the mixturecontains from about 3% to about 20% (vol/vol) of the co-solvent, morepreferably about 5% to about 10% of the co-solvent. Preferably, theco-solvent is selected from the group consisting of DMF, butanol andacetone. Preferably, the hydrocarbon is an aromatic hydrocarbon, morepreferably xylene, benzene, toluene and chlorobenzene, and mostpreferably toluene.

In another aspect, the present invention provides a process forracemizing (R) clopidogrel comprising reacting (R) clopidogrel with acatalytic amount of a base in a solvent to convert a portion of the (R)clopidogrel to (S) clopidogrel. Preferred bases are sodium t-butoxide,potassium t-butoxide, diisopropylamide, sodium hydride, potassiumhydride, sodium methoxide and potassium methoxide. Preferably, thesolvent is a hydrocarbon as described above. Preferably, the racemizingis carried out at a temperature of less than about 20° C., morepreferably at a temperature of about 0° C.

In another aspect, the present invention provides a process forpreparing a pharmaceutically acceptable salt of (S) clopidogrelcomprising the steps of reacting a first mixture of (R) and (S)clopidogrel with levorotatory camphor sulfonic acid in a mixture of a C₅to a C₁₂ hydrocarbon and a suitable co-solvent to precipitate a first(S) clopidogrel camphor sulfonate, racemizing (R) clopidogrel remainingin the mixture of the hydrocarbon and the co-solvent by reaction with acatalytic amount of a base to obtain a second mixture of (R) and (S)clopidogrel, precipitating both forms of clopidogrel from the secondmixture of (R) and (S) clopidogrel by adding an acid to form a salt,converting the salt to a free base, repeating the first step of theprocess to obtain a second (S) clopidogrel camphor sulfonate from thefree base and converting the first and second (S) clopidogrel camphorsulfonate to a pharmaceutically acceptable salt of (S) clopidogrel.

In another aspect, the present invention provides a process forpreparing a pharmaceutically acceptable salt of (S) clopidogrelcomprising the steps of reacting a first mixture of (R) and (S)clopidogrel with levorotatory camphor sulfonic acid in a mixture of a C₅to a C₁₂ hydrocarbon and a suitable co-solvent to precipitate a first(S) clopidogrel camphor sulfonate, racemizing the (R) clopidogrelremaining in the mixture of the hydrocarbon and the co-solvent byreaction with a catalytic amount of a base to obtain a second mixture of(R) and (S) clopidogrel, reacting the second mixture of (R) and (S)clopidogrel with levorotatory camphor sulfonic acid to precipitate asecond (S) clopidogrel camphor sulfonate and converting the first andthe second (S) clopidogrel camphor sulfonate to a pharmaceuticallyacceptable salt of (S) clopidogrel.

In another aspect, the present invention provides a process forpreparing (S) enantiomer of clopidogrel bisulfate comprising the stepsof reacting a solution of (R) and (S) clopidogrel in toluene with asolution of levorotatory camphor sulfonic acid in DMF, thereby forming afirst clopidogrel (S) camphor sulfonate as a precipitate, removing theDMF and excess camphor sulfonic acid, racemizing the (R) clopidogrel byreaction with a catalytic amount of a base in the toluene to form amixture of clopidogrel (R) and (S), reacting the mixture of (R) and (S)clopidogrel with levorotatory camphor sulfonic acid in the toluene,thereby forming a second (S) clopidogrel camphor sulfonate as aprecipitate and converting the first and the second (S) clopidogrelcamphor sulfonate to (S) clopidogrel bisulfate.

In another aspect, the present invention provides a process forpreparing (S) clopidogrel bisulfate comprising the steps of reacting asolution of clopidogrel (R) and (S) in toluene with a solution oflevorotatory camphor sulfonic acid in DMF, thereby forming a firstclopidogrel (S) camphor sulfonate as a precipitate, removing the DMF andexcess camphor sulfonic acid, racemizing the (R) clopidogrel remainingin the toluene by reaction with a catalytic amount of a base in thetoluene to form a mixture of (R) and (S) clopidogrel, adding sulfuricacid to the mixture of (R) and (S) clopidogrel to precipitateclopidogrel (R) and (S) as a bisulfate, converting the bisulfate to afree base, repeating the first step of the process to obtain a second(S) clopidogrel camphor sulfonate from the free base and converting thefirst and the second (S) clopidogrel camphor sulfonate to (S)clopidogrel bisulfate.

In another aspect, the present invention provides a process forpreparing (S) clopidogrel bisulfate comprising the steps of reacting asolution of (R) and (S) clopidogrel in toluene with a solution oflevorotatory camphor sulfonic in DMF, thereby forming (S) clopidogrelcamphor sulfonate as a precipitate and converting (S) clopidogrelcamphor sulfonate to clopidogrel bisulfate.

In another aspect the present invention provides a process for preparing(S) clopidogrel free base or a pharmaceutically acceptable salt thereofcomprising the steps of reacting a mixture of (R) and (S) clopidogrelfree base with levorotatory camphor sulfonic acid in a C₅ to a C₁₂hydrocarbon to precipitate (S) clopidogrel camphor sulfonate andconverting (S) clopidogrel camphor sulfonate to clopidogrel free base ora pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a process forpreparing a pharmaceutically acceptable salt of (S) clopidogrelcomprising the steps of reacting a mixture of (R) and (S) clopidogrelwith levorotatory camphor sulfonic acid in a C₅ to a C₁₂ aromatichydrocarbon to precipitate (S) clopidogrel camphor sulfonate, racemizingthe (R) clopidogrel remaining in the hydrocarbon by reaction with acatalytic amount of a base in the hydrocarbon to obtain a mixture of (R)and (S) clopidogrel, recovering the (S) clopidogrel and converting the(S) clopidogrel to a pharmaceutically acceptable salt.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides a pictorial illustration of the various examples.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides facile processes for separation of the(S) enantiomer of clopidogrel from a racemic mixture of the enantiomers,and recycling the (R) enantiomer after the separation step to producemore of the (S) enantiomer. The clopidogrel used in the presentinvention can be synthesized according to the disclosed methods of thepresent invention or any method known in the art.

The present invention uses bases for freeing the base of clopidogrel ordeprotonating clopidogrel for racemization. One of skill in the artwould appreciate that many bases can be used to free the base ordeprotonate clopidogel. Examples of bases include, for example, anorganic amine, an alkoxide, an alkali metal hydroxide, an alkaline earthmetal hydroxide, an alkali metal hydride, an alkaline earth metalhydride or an alkali or alkaline earth metal carbonate orhydrogencarbonate salt. Specific examples of bases include, for example,1,8-bis(N,N-dimethylamino)napthalene, sodium methoxide, sodium ethoxide,sodium phenoxide, sodium hydroxide, potassium hydroxide, calciumhydroxide, magnesium hydroxide, sodium hydride, potassium hydride,calcium hydride, sodium carbonate, potassium carbonate, sodiumhydrogencarbonate, potassium hydrogencarbonate, calcium carbonate andbasic alumina. The preferred base and its concentration can varydepending on the desired task. For example, when deprotonating, a strongbase such as an alkoxide is preferred over a weak base such as an amine.Preferred bases for racemization by deprotonation are lithiumdiusopropylamide (“LDA”), potassium hydride, sodium hydride, sodiummethoxide and t-butoxide.

To separate the (S) enantiomer of clopidogrel bisulfate from the racemicmixture, a racemic mixture of clopidogrel free base is first prepared byreacting the bisulfate salt with a base. Preferred bases are non-organicbases, particularly sodium/potassium carbonate or hydroxide.

Any formed sulfate, particularly sodium sulfate, can be removed byconventional techniques such as filtration. The free base is thencrystallized from a mixture of a C₅ to a C₁₂ hydrocarbon and a suitableco-solvent in the presence of levorotatory camphor sulfonic acid.

In a preferred embodiment, a mixture of clopidogrel bisulfate is treatedwith a slight excess of sodium hydroxide in a C₅ to a C₁₂ hydrocarbon.The mixture used can have a higher proportion of one of the enantiomersin respect to the other, or be a racemic mixture. The resulting solutionof clopidogrel free base in the hydrocarbon is then added to a solutionof levorotatory camphor sulfonic acid in a suitable co-solvent of thehydrocarbon used. Suitable co-solvents are those that are miscible inthe C₅ to a C₁₂ hydrocarbon used and allow for crystallization of (S)clopidogrel camphor sulfonate. Preferably, the co-solvent can beseparated from the hydrocarbon by washing with water. Examples of suchsuitable solvents include C₁ to C₄ alcohols such as methanol, ethanol,iso-propanol and butanol, lower ketones such as acetone and lower amidessuch as dimethylformamide (“DMF”). Butanol for example, despite itsrelatively low miscibility with water, can be washed continuously andremoved. The use of DMF as a co-solvent is preferred, particularly in amixture with toluene. Preferred C₅ to C₁₂ hydrocarbons are substitutedand unsubstituted aromatic hydrocarbons, such as benzene, xylene,toluene and chlorobenzene. A preferred aromatic hydrocarbon is toluene.In various embodiments, the combination of toluene with acetone, DMF andbutanol may be used, with the combination of DMF/toluene beingillustrated in the present invention.

The resulting mixture of the hydrocarbon and the co-solvent is at most50%, more preferably from a 3% to about a 20%, most preferably fromabout a 5% to about a 10% co-solvent:hydrocarbon (vol/vol) mixture. Theamount of co-solvent, such as DMF, influences the resolution rate andthe diastereomic excess obtained. An excess amount of DMF slows down thecrystallization process and lowers the yield.

The (S) enantiomer of clopidogrel is then crystallized out of thesolution, leaving substantially the (R) enantiomer in the solution. Theratio of clopidogrel free base to camphor sulfonic acid is preferablyfrom about a 1/0.6 to 1/0.8, more preferably about a 1/0.6 (mole/mole)of clopidogrel:camphor sulfonic acid. The ratio is in relation to bothenantiomers of clopidogrel. The crystals are substantially in the formof (S) clopidogrel camphor sulfonate. Without being bound by any theory,it is believed that the (R) enantiomer, being unable to form a salt withlevorotatory camphor sulfonic acid, remains in the solution. While, (S)clopidogrel camphor sulfonate, having low solubility for the solvent,crystallizes out of the solution. To accelerate crystallization, thesolution may be seeded or the temperature of the solution reduced.Preferably the temperature is reduced to about 5° C. to about 25° C.,with about 15° C. being preferred. The present invention encompassesboth embodiments where crystallization is induced, or whencrystallization occurs spontaneously upon contact.

The solution can be monitored during the crystallization process toensure crystallization of substantially all of the (S) enantiomer. In apreferred embodiment, the solution is monitored with a polarimeter. Foroptimal result, the crystallization process is stopped when the opticalrotation of the solution (mother liquor) remains constant for at leastabout 1 hour.

In another embodiment, a co-solvent is not used. Rather a hydrocarbon asdescribed above is used as a solvent free of a co-solvent for reactionof clopidogrel free base with levorotatory camphor sulfonic, followed byprecipitation. Preferably, the hydrocarbon contains only traces of othersolvents, most preferably the hydrocarbon is pure.

The (S) clopidogrel camphor sulfonate can then be converted to (S)clopidogrel bisulfate in a routine fashion. The free base is firstliberated by treating the camphor sulfonate with a base, as describedabove, preferably with sodium/potassium bicarbonate. Preferably a weakor dilute base is used to avoid racemization. In a preferred method, the(S) clopidogrel camphor sulfonate is dissolved in a mixture of water andan ester such as ethyl acetate or a ketone. Sodium/potassium bicarbonateand/or sodium hydroxide is then added to basify the water, resulting inthe free base of (S) clopidogrel. The free base is then extracted out ofthe water with a suitable organic solvent, such as dichloromethane orethylacetate, followed by concentration of the organic phase. Theresidue is added to a suitable solvent, such as acetone, in the presenceof sulfuric acid, resulting in the precipitation of clopidogrelbisulfate.

In one embodiment, illustrated in Example 9, clopidogrel hydrogensulfateForm I is prepared from clopidogrel camphour sulfonate by addition to awater/ethyl acetate mixture. A solution of sodium hydroxide is thenadded to increase the pH, preferably at a temperature of from about 10°C. to about 20° C., with about 15° C. being preferred. The pH of thesolution is then adjusted with sodium carbonate, preferably to about 8,and the organic phase is separated. The ethyl acetate is then removed,preferably under reduced pressure, to obtain a residue. The residue isdissolved in acetone, to which sulfuric acid is added to obtain thehydrogensulfate salt. Preferably, the solution is cooled to atemperature of from about 10° C. to about 20° C. The solution may alsobe seeded with Form I and stirred at about room temperature for a fewhours. Clopidogrel hydrogensulfate Form I then precipitates from thesolution, which may be separated by techniques well known in the art,such as filtration.

The present invention also provides for processes which allow forrecycling the (R) enantiomer left in the mother liquor. The processes ofthe present invention accomplish this recycling process by racemizationof the (R) enantiomer into a mixture of (S) and (R) enantiomers, andseparating the two enantiomers as described above. As one of skill inthe art would appreciate, the recycling step can be repeated many timesto recycle as much of the (R) enantiomer as possible. A small portion ofthe (R) enantiomer may be purged each time to improve overall efficiencyof the process.

The racemization step can be carried out in the same or differentsolvent as prior steps. The solvent used for racemization however shouldbe one that avoids reactivity problems with strong bases. Suchreactivity can occur for example when using a ketone. DMF however couldbe used in the racemization step, but the subsequent camphor sulfonatesalt is soluble in DMF. The substitution of DMF with another solvent,after racemization, would be needed for optimal crystallization. Apreferred solvent for racemization is a hydrocarbon as described above.

The (R) enantiomer is racemized by treatment with a base. As usedherein, “racemizing (R) clopidogrel” refers to obtaining an opticallyinactive mixture, or stopping the racemization process at any point toobtain an unequal mixture of the forms. The (R) clopidogrel can becontacted/reacted with a base in the presence or absence of (S)clopidogrel, i.e., reacting (R) clopidogrel with a base covers bothembodiments. For example, it is unlikely that 100% of (S) clopidogrelwould precipitate as the camphor sulfonate, thus leaving some (S)clopidogrel in the solution during the racemization step.

The mother liquor containing the (R) enantiomer is preferably washedfirst to remove any remaining camphor sulfonic acid. A preferred methodof removing camphor sulfonic acid is by making the mother liquoralkaline, such as by using an aqueous solution of sodium bicarbonate.The organic phase is then separated from the resulting aqueous phase.The washing removes the co-solvent, leaving only traces of theco-solvent remaining during racemization.

A base can be used to racemize the (R) clopidogrel. A preferredinorganic base is sodium/potassium hydroxide, while a preferred organicbase is a C₁ to a C₄ alkoxide. A particularly preferred base issodium/potassium t-butoxide, which is more effective thansodium/potassium methoxide.

Bases, particularly alkoxides such as t-butoxide are highly reactivetowards moisture, and in order for the t-butoxide added to be effective,the organic phase preferably has a low water content. Preferably, thewater content of the organic phase is less than or equal to about 0.1%,more preferably 0.05%, as determined by the Karl Fischer method. Afterachieving an acceptable water level, a catalytic amount of potassiumt-butoxide is added to the organic phase. Preferably, the amount ofpotassium t-butoxide is from about 0.01 to about 0.15 moles relative toboth forms of clopidogrel, more preferably about 0.05 moles. The molarratio also generally applies to other bases. Preferably, the t-butoxideis added to the organic phase at a temperature of less than about 20°C., more preferably at a temperature less than about 10° C., even morepreferably at a temperature of less than about 5° C. and most preferablyat a temperature of about 0° C.

After addition of the t-butoxide, some of the (R) enantiomer converts tothe (S) enantiomer, resulting in a mixture of the forms. A small amountof time, less than about one hour, more likely less than about 30minutes is often sufficient to allow for the conversion. Theracemization results in an optically inactive mixture.

After obtaining a mixture of the forms, the recovery of the forms can bedone by conventional techniques. First, the t-butoxide is neutralized,for example by adding an acid. An example of an acid is acetic acid,whose addition results in formation of t-butanol. The organic phase isthen preferably washed with water to remove the alcohol, the formed saltand any residual acid.

The organic phase is then preferably concentrated. Conventionaltechniques, such as evaporation under reduced pressure, heating orincreasing surface area (i.e. rotary evaporator) can be used toconcentrate the organic phase. The result of the concentration ispreferably a thick oil.

The racemic mixture can then be crystallized by adding the oil to anorganic solvent in the presence of sulfuric acid or another acid.Examples of suitable solvents include lower alcohols, esters, ethers andketones (such as acetone). The preferred solvent may vary depending onwhether the camphor sulfonate or the bisulfate is crystallized out ofthe solution. In a preferred embodiment, the oil is added to atoluene/DMF mixture, followed by addition of sulfuric acid, resulting incrystallization of a racemic mixture of clopidogrel bisulfate. The (S)enantiomer can then be separated from the racemic mixture as describedabove, i.e., by conversion to clopidogrel free base, precipitation as(S) clopidogrel camphor sulfonate salt and conversion to the desirableacid addition salt.

In another embodiment, the oil is added to a solvent such as acetone ora toluene/DMF mixture in the presence of levorotatory camphor sulfonicacid, resulting in precipitation of (S) clopidogrel camphor sulfonate.The (S) clopidogrel camphor sulfonate is then converted to the bisulfateby conventional techniques.

The present invention allows for a continuous process for preparing (S)clopidogrel, wherein (S) clopidogrel is constantly removed, whileadditional (S) clopidogrel is added as a starting material or fromrecycling of the (R) enantiomer. The continuous recycling process allowsfor an efficient process on industrial scale. In a preferred embodiment,the racemic mixture generated by recycling the (R) enantiomer iscrystallized out as a bisulfate salt or another salt, and used as astarting material by conversion to the free base. In another embodiment,the (S) clopidogrel is crystallized out of the recycled mixture ascamphor sulfonate, and then converted to the bisulfate. A small portionof the waste material may be purged as the process proceeds.

The processes of the present invention can be used to prepare anypharmaceutically acceptable salt of clopidogrel. These processes havebeen illustrated so far with the bisulfate salt. Examples of otherpharmaceutically acceptable salts are disclosed in U.S. Pat. No.4,847,265, incorporated herein by reference: acetic, benzoic, fumaric,maleic, citric, tartaric, gentisic, methane-sulfonic, ethanesulfonic,benzenesulfonic and laurylsulfonic, taurocholate and hydrobromide salts.Of these, taurocholate and hydrobromide salts, like the bisulfate salt,exhibit better pharmaceutical properties. The processes for preparingthese other salts is the same as that for the bisulfate salt exceptinstead of sulfuric acid another acid is added to obtain the desiredacid addition salt. These salts can be converted to the free base in asimilar manner as that discussed for the bisulfate salt.

As a platelet inhibitor, clopidogrel is effective at suppressing thelethal effects of blood clotting. Platelet aggregation often occursaround damaged blood vessels. The blood vessels may only have minorfissures or plaques to induce platelet aggregation.

Platelet aggregation leads to the blockage of arteries, thus increasingthe risk of primary and secondary strokes and heart attacks. Byinhibiting platelet aggregation, clopidogrel bisulfate reduces the riskof heart attacks and strokes. Clopidogrel is particularly effective inthe secondary prevention of ischemic events, which are defined in theart as a decrease in the blood supply to a bodily organ, tissue, or partcaused by constriction or obstruction of the blood vessels.

Pharmaceutical compositions of the present invention contain the (S)enantiomer of clopidogrel bisulfate, optionally in a mixture with otheractive ingredients. In addition to the active ingredient(s), thepharmaceutical compositions of the present invention may contain one ormore excipients. Excipients are added to the composition for a varietyof purposes.

Diluents increase the bulk of a solid pharmaceutical composition, andmay make a pharmaceutical dosage form containing the composition easierfor the patient and care giver to handle. Diluents for solidcompositions include, for example, microcrystalline cellulose (e.g.Avicel®), microfine cellulose, lactose, starch, pregelitinized starch,calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, tdextrose, dibasic calcium phosphate dihydrate, tribasic calciumphosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin,mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride,powdered cellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a dosage form,such as a tablet, may include excipients whose functions include helpingto bind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions includeacacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulosesodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenatedvegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g.Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquidglucose, magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinizedstarch, sodium alginate and starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach may be increased by the addition of a disintegrantto the composition. Disintegrants include alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellosesodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum,magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, sodium starch glycolate (e.g. Explotab®) andstarch.

Glidants can be added to improve the flowability of a non-compactedsolid composition and to improve the accuracy of dosing. Excipients thatmay function as glidants include colloidal silicon dixoide, magnesiumtrisilicate, powdered cellulose, starch, talc and tribasic calciumphosphate.

When a dosage form such as a tablet is made by the compaction of apowdered composition, the composition is subjected to pressure from apunch and dye. Some excipients and active ingredients have a tendency toadhere to the surfaces of the punch and dye, which can cause the productto have pitting and other surface irregularities. A lubricant can beadded to the composition to reduce adhesion and ease the release of theproduct from the dye. Lubricants include magnesium stearate, calciumstearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenatedcastor oil, hydrogenated vegetable oil, mineral oil, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate,stearic acid, talc and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that may be included in the composition ofthe present invention include maltol, vanillin, ethyl vanillin, menthol,citric acid, fumaric acid, ethyl maltol, and tartaric acid.

Solid and liquid compositions may also be dyed using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present invention,clopidogrel bisulfate and any other solid excipients are dissolved orsuspended in a liquid carrier such as water, vegetable oil, alcohol,polyethylene glycol, propylene glycol or glycerin.

Liquid pharmaceutical compositions may contain emulsifying agents todisperse uniformly throughout the composition an active ingredient orother excipient that is not soluble in the liquid carrier. Emulsifyingagents that may be useful in liquid compositions of the presentinvention include, for example, gelatin, egg yolk, casein, cholesterol,acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer,cetostearyl alcohol and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention may alsocontain a viscosity enhancing agent to improve the mouth-feel of theproduct and/or coat the lining of the gastrointestinal tract. Suchagents include acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch tragacanthand xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol and invert sugar may be added toimprove the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxy toluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improvestorage stability.

According to the present invention, a liquid composition may alsocontain a buffer such as guconic acid, lactic acid, citric acid oracetic acid, sodium guconate, sodium lactate, sodium citrate or sodiumacetate.

Selection of excipients and the amounts used may be readily determinedby the formulation scientist based upon experience and consideration ofstandard procedures and reference works in the field.

The solid compositions of the present invention include powders,granulates, aggregates and compacted compositions. The dosages includedosages suitable for oral, buccal, rectal, parenteral (includingsubcutaneous, intramuscular, and intravenous), inhalant and ophthalmicadministration. Although the most suitable administration in any givencase will depend on the nature and severity of the condition beingtreated, the most preferred route of the present invention is oral. Thedosages may be conveniently presented in unit dosage form and preparedby any of the methods well-known in the pharmaceutical arts.

Dosage forms include solid dosage forms like tablets, powders, capsules,suppositories, sachets, troches and losenges, as well as liquid syrups,suspensions and elixirs.

The dosage form of the present invention may be a capsule containing thecomposition, preferably a powdered or granulated solid composition ofthe invention, within either a hard or soft shell. The shell may be madefrom gelatin and optionally contain a plasticizer such as glycerin andsorbitol, and an opacifying agent or colorant.

The active ingredient and excipients may be formulated into compositionsand dosage forms according to methods known in the art.

A composition for tableting or capsule filling may be prepared by wetgranulation. In wet granulation, some or all of the active ingredientsand excipients in powder form are blended and then further mixed in thepresence of a liquid, typically water, that causes the powders to clumpinto granules. The granulate is screened and/or milled, dried and thenscreened and/or milled to the desired particle size. The granulate maythen be tableted, or other excipients may be added prior to tableting,such as a glidant and/or a lubricant.

A tableting composition may be prepared conventionally by dry blending.For example, the blended composition of the actives and excipients maybe compacted into a slug or a sheet and then commuted into compactedgranules. The compacted granules may subsequently be compressed into atablet.

As an alternative to dry granulation, a blended composition may becompressed directly into a compacted dosage form using directcompression techniques. Excipients that are particularly well suited fordirect compression tableting include microcrystalline cellulose, spraydried lactose, dicalcium phosphate dihydrate and colloidal silica. Theproper use of these and other excipients in direct compression tabletingis known to those in the art with experience and skill in particularformulation challenges of direct compression tableting.

A capsule filling of the present invention may comprise any of theaforementioned blends and granulates that were described with referenceto tableting, however, they are not subjected to a final tableting step.

Capsules, tablets and lozenges, and other unit dosage forms preferablycontain a base equivalent of about 75 mg, which is about 98 grams ofclopidogrel bisulfate. The unit dosage form as used herein refers to theamount of the various forms of clopidogrel contained in the vehicle ofadministration, such as a tablet or a capsule. In a preferredembodiment, the unit dosage in a tablet for oral administration containsa base equivalent of about 25 mg to 150 mg. Most preferably, it is about75 mg base equivalent. One skilled in the art would appreciate thatother unit dosages may be made as necessary in a routine fashion.

Instrumentation Used:

The polarimiter used was Perkin Elmer® 241, and Karl Fischer analysiswas done with Metrohm® 703.

The following examples further illustrate the present invention:

EXAMPLES Example 1

Synthesis of Tetrahydrothienopyridine Hydrochloride

2-thienylethiamine was reacted with formaldehyde to give thecorresponding formimine, which was then added to a solution ofhydrochloric acid in DMF, resulting in cyclization totetrahydrothienopyridine hydrochloride. The DMP used was anhydrous,KF≦0.05%, to avoid formimine hydrolysis.

Example 2

Synthesis of Racemic Clopidogrel

Tetrahydrothienopyridine hydrochloride from Example 1 was reacted withα-bromo-2-chlorophenyl acetic acid methyl ester in acetone in thepresence of potassium carbonate to give racemic clopidogrel. Afterinorganic salt filtration, the product was recovered as bisulfate, byaddition of sulfuric acid.

Example 3

Preparation of Clopidogrel Free Base from Bisulfate

Clopidogrel bisulfate was suspended in a mixture of toluene and water.The pH of the suspension was adjusted to 11-12 with 50% sodium hydroxidesolution. The reaction mixture was kept at 35° C., followed by phaseseparation. The organic phase was filtered through decolorizing clay.The filtrate was evaporated under vacuum until all of the toluene wasremoved. The resulting oil contained clopidogrel free base.

Example 4

Resolution by Camphorsulfonic Salt Formation

A reactor was charged with racemic clopidogrel of Example 3 and toluene.Another reactor was charged with DMF and (−)-(R)-camphorsulfonic acid(CSA/Rac clopidogrel=0.6/1 mole/mole) and heated to 30° C. The toluenesolution was added to the DMF/(−)-(R)-camphorsulfonic acid solution. Allreagents were measured on the basis of the calculated amount of racemicclopidogrel used.

The batch solution was maintained at 30° C. and seeded with (+)Clopidogrel camphor sulfonate, then cooled to 15° C. to affectcrystallization of the product. The rotation of the filtrates from afiltered sample was measured. Samples were taken every 30 minutes untiltwo of the results taken were within 0.01 of each other, within range of−0.455±0.035 or until the rotation began to decrease. The product wasfiltered, washed with toluene, then dried under vacuum at ≦35° C.

Example 5

Bis Resolution (Camphorsulfonic Salt Formation)

(+)-(S)-a-(2-Chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-C]Pyridyl-5-acetic acid methyl ester, (−) CSA salt was suspended inacetone at reflux for 1 hour, cooled to room temperature, filtered anddried under vacuum at a temperature of 35° C.

Example 6

Preparation of Clopidogrel Bisulfate Form 1 from the Camphor SulfonateSalt

(+) Clopidogrel (−) CSA salt was added to ethyl acetate and water. Nextsodium hydroxide was charged to the batch followed by sodiumbicarbonate. The organic phase was separated and washed with water, andthen decolorized with charcoal. Once the charcoal was filtered, thebatch was concentrated. The residue was dissolved in acetone, and thensulfuric acid was added followed by clopidogrel polymorph seed. Thecrystals were aged under stirring, then filtered and washed withacetone. The crystals were then dried under vacuum at a temperature ofless than 25° C.

Example 7

Racemization and Racemic Bisulfate Recovery

The mother liquor from Example 4 was washed with 6% sodium bicarbonatesolution. The two resulting phases were separated. After separation, theorganic phase was dried by azeotropic distillation under reducedpressure until KF≦0.05%. A catalytic amount of potassium tert-butoxidewas added at 0° C., and racemization occurred within 20 minutes. Afterneutralization of potassium tert-butoxide with acetic acid, and washingwith water, the organic solution was concentrated until a thick oil wasobtained. After dissolution in acetone, sulfuric acid was added and theracemic clopidogrel was recovered as bisulfate.

Example 8

Racemization and (S) Clopidogrel Camphor Sulfonate Recovery

The mother liquor from Example 4 is washed with 6% sodium bicarbonatesolution. The two resulting phases are separated. After separation, theorganic phase is dried by azeotropic distillation under reduced pressureuntil KF≦0.05%. A catalytic amount of potassium tert-butoxide is addedat 0° C., and racemization occurs within 20 minutes. Afterneutralization of potassium tert-butoxide with acetic acid, and washingwith water, the organic solution is concentrated until a thick oil isobtained. After dissolution in acetone, camphor sulfonic acid is addedand (S) clopidogrel is recovered as camphor sulfonate. The (S)clopidogrel camphor sulfonate is then added to a base, followed byaddition of an acid to obtain the desired acid addition salt.

Example 9

Preparation of Clopidogrel Hydrogensulfate Form I

(+) Clopidogrel (−) Camphor Sulfonate (90 g) was dissolved in 462 ml ofan ethylacetate/deionized water mixture (60:40 v/v). A solution of 30%sodium hydroxide (20 g) was added while maintaining the temperature atabout 15° C. The pH of the mixture was adjusted to about 8.1 with NaHCO₃(9.2 g), and then phase separation was performed. The organic phase waswashed with DI water and then treated with active carbon. Afterfiltration of the active carbon, the ethyl acetate was removed undervacuum (at RT 30mmHg). The residue was diluted with acetone (348 ml) andthe resulting solution cooled to about 15° C. 96% H₂SO₄ (6.2 gr) wasadded while cooling. The mixture was seeded with clopidogrel hydrogensulfate Form I and stirred for about 7 hours at 25° C. The precipitateproduct was filtered, washed with acetone and dried under vacuum to give62.4 grams of (+) (S) Clopidogrel bisulfate form I.

Having thus described the invention with reference to particularpreferred embodiments and illustrative examples, those in the art canappreciate modifications to the invention as described and illustratedthat do not depart from the spirit and scope of the invention asdisclosed in the specification. The Examples are set forth to aid inunderstanding the invention but are not intended to, and should not beconstrued to, limit its scope in any way. The examples do not includedetailed descriptions of conventional methods. Such methods are wellknown to those of ordinary skill in the art and are described innumerous publications. All references mentioned herein are incorporatedin their entirety.

1. A process for preparing (S) clopidogrel free base or apharmaceutically acceptable salt thereof comprising the steps of: a)reacting a mixture of (R) and (S) clopidogrel free base withlevorotatory camphor sulfonic acid in a mixture of a C₅ to a C₁₂hydrocarbon and a suitable co-solvent to precipitate (S) clopidogrelcamphor sulfonate; and b) converting (S) clopidogrel camphor sulfonateto clopidogrel free base or a pharmaceutically acceptable salt thereof.2. The process of claim 1, wherein the salt is a bisulfate salt.
 3. Theprocess of claim 1, wherein the mixture contains from about 3% to about20% (vol/vol) of the co-solvent.
 4. The process of claim 3, wherein themixture contains from about 5% to about 10% of the co-solvent.
 5. Theprocess of claim 1, wherein the co-solvent is selected from the groupconsisting of DMF, butanol and acetone.
 6. The process of claim 1,wherein the hydrocarbon is an aromatic hydrocarbon.
 7. The process ofclaim 6, wherein the aromatic hydrocarbon is selected from the groupconsisting of xylene, benzene, toluene and chlorobenzene.
 8. The processof claim 7, where the hydrocarbon is toluene.
 9. The process of claim 1,comprising a preliminary step of reacting a mixture of clopidogrel (R)and (S) bisulfate with a base.
 10. A process for racemizing (R)clopidogrel comprising reacting (R) clopidogrel with a catalytic amountof a base in a solvent to convert a portion of the (R) clopidogrel to(S) clopidogrel.
 11. The process of claim 10, wherein the catalyticamount is less than about 0.15 moles relative to clopidogrel.
 12. Theprocess of claim 10, fuirther comprising a step of crystallizing apharmaceutically acceptable salt or a camphor sulfonate salt of the (S)clopidogrel.
 13. The process of claim 12, wherein the salt is abisulfate salt.
 14. The process of claim 10, wherein the base isselected from the group consisting of sodium t-butoxide, potassiumt-butoxide, diisopropylamide, sodium hydride, potassium hydride, sodiummethoxide and potassium methoxide.
 15. The process of claim 10, whereinthe solvent is a C₅ to a C₁₂ hydrocarbon.
 16. The process of claim 15,wherein the hydrocarbon is an aromatic hydrocarbon.
 17. The process ofclaim 16, wherein the aromatic hydrocarbon is selected from the groupconsisting of xylene, benzene, toluene and chlorobenzene.
 18. Theprocess of claim 17, where the hydrocarbon is toluene.
 19. The processof claim 10, wherein the racemizing is carried out at a temperature ofless than about 20° C.
 20. The process of claim 19, wherein thetemperature is about 0° C.